This application is a National Stage application under 35 U.S.C. 371 of PCT/EP99/09155 filed Nov. 22, 1999, which claims priority from EP 98.203.930.7, filed Nov. 23, 1998.
The present invention concerns IL-5 inhibiting 6-azauracil derivatives useful for treating eosinophil-dependent inflammatory diseases; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.
Eosinophil influx, leading to subsequent tissue damage, is an important pathogenic event in bronchial asthma and allergic diseases. The cytokine interleukin-5 (IL-5), produced mainly by T lymphocytes as a glycoprotein, induces the differentiation of eosinophils in bone marrow and, primes eosinophils for activation in peripheral blood and sustains their survival in tissues. As such, IL-5 plays a critical role in the process of eosinophilic inflammation. Hence, the possibility that inhibitors of IL-5 production would reduce the production, activation and/or survival of eosinophils provides a therapeutic approach to the treatment of bronchial asthma and allergic diseases such as, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and also other eosinophil-dependent inflammatory diseases.
Steroids, which strongly inhibit IL-5 production ill vitro, have long been used as the only drugs with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds having the ability to inhibit IL-5 production in human T-cells and which have little or no adverse reactions.
U.S. Pat. No. 4,631,278 discloses xcex1-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitriles and U.S. Pat. No. 4,767,760 discloses 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoal activity, in particular, anti-coccidial activity. EP 831,088 discloses 1,2,4-triazine-3,5-diones as anticoccidial agents. Unexpectedly, the 6-azauracil derivatives of the present invention prove to be potent inhibitors of the production of IL-5.
The present invention is concerned with the compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
p represents an integer being 0, 1, 2 or 3;
q represents an integer being 0, 1, 2, 3, 4 or 5;
xe2x80x94Axe2x80x94Bxe2x80x94 represents xe2x80x94(CH2)rxe2x80x94, xe2x80x94(CH2)txe2x80x94Oxe2x80x94, xe2x80x94(CH2)txe2x80x94S(xe2x95x90O)uxe2x80x94 or xe2x80x94(CH2)txe2x80x94NR3xe2x80x94;
r represents 2, 3 or 4;
each t independently represents 1, 2 or 3;
u represents 0, 1 or 2;
X1 represents O, S, NR3 or a direct bond;
each R1 independently represents C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with Het3, R6 or NR7 R8;
R2 represents aryl, Het1, C3-7cycloalkyl, cyano, C1-6alkyl, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15 or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono-or di(C1-4alkyl)amino, C1-6alkyloxy, C1-6alkylsulfonyloxy, C1-6alkyloxycarbonyl, C3-7cycloalkyl, aryl, aryloxy, arylthio, Het1, Het1 Het1thio and xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15;
R3 represents hydrogen or C1-4alkyl;
each R4 independently represents C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6,
NR7R8 or C1-4alkyl substituted with Het3, R6 or NR7R8;
each R15 independently represents hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl or C1-6alkyl substituted with aryl, halo, hydroxy or Het1;
where X2 is a direct bond, R15 may also be halo or Het1;
where X2 is NR5, R15 may also be hydroxy;
where X2 is C(xe2x95x90O)xe2x80x94NHxe2x80x94NH or NHxe2x80x94NHxe2x80x94C(xe2x95x90O), R15 may be replaced by R11; R5 represents hydrogen, C1-6alkyl, C1-6alkyloxy or arylC1-6alkyl;
each Q independently represents O, S or NR3;
each X2 independently represents O, S, NR5, C(xe2x95x90O)xe2x80x94NHxe2x80x94NH, NHxe2x80x94NHxe2x80x94C(xe2x95x90O) or a direct bond;
each R6 independently represents C1-6alkylsulfonyl, aminosulfonyl, mono- or di-(C1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC1-6alkylsulfonyl, C1-6alkylsulfinyl, phenylC1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, Nxe2x80x94C1-4alkylxe2x80x94N-piperidinylaminosulfonyl or mono-or di(C1-4alkyl)aminoC1-4alkylsulfonyl;
each R7 and each R8 are independently selected from hydrogen, C1-4alkyl, hydroxy-C1-4alkyl, dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, arylcarbonyl, Het3carbonyl, C1-4alkylcarbonyloxy-C1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 and R6;
Y represents O, S, NR3, or S(O)2;
R9 and R10 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het3carbonyl, C1-4alkylcarbonyloxy-C1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, mono-or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediylxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediylxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 and R6;
each R11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C1-4alkyloxy, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(xe2x95x90O)NR7R8, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediylxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, aryl, aryloxy, arylcarbonyl, C3-7cycloalkyl, C3-7cycloalkyloxy, phthalimide-2-yl, Het3, Het4 and C(xe2x95x90O)Het3;
R1 and R2 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, phenylcarbonyl, C1-4alkylcarbonyloxyC1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediylxe2x80x94C(O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14 and R6;
each R14 independently represents hydrogen, C1-4alkyl, C3-7cycloalkyl, aminocarbonylmethylene, mono-or di(C1-4alkyl)aminocarbonylmethylene, mono-or di(C3-7cycloalkyl)aminocarbonylmethylene, azetidin-1-ylcarbonylmethylene, pyrrolidin-1-yl-carbonylmethylene, piperidin-1-ylcarbonylmethylene or homopiperidin-1-ylcarbonylmethylene;
aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C1-4alkyl, C3-7cyclo-alkyl, C1-4alkyloxy, formyl, polyhaloC1-4alkyl, NR9R10, C(xe2x95x90O)NR9R10, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, R6, xe2x80x94Oxe2x80x94R6, phenyl, Het3, C(xe2x95x90O)Het3 and C1-4alkyl substituted with hydroxy, C1-4alkyloxy, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 or NR9R10;
Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with one or two substituents independently selected from Het2 and R11;
Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl optionally substituted with one or two substituents independently selected from R11;
Het3 represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, piperidinyl, NR12R13, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, R6 and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy, phenyl, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Yxe2x80x94C1-4alkanediylxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, R6 and NR12R13;
Het4 represents a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; polyhaloC1-4alkyl is defined as polyhalosubstituted C1-4alkyl, in particular C1-4alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; polyhaloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl. The term C1-4alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C2-6alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 2 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like.
Het1, Het2, Het3 and Het4 are meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het1, Het2, Het3 and Het4, for instance, pyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.
The heterocycles represented by Het1, Het2, Het3 and Het4 may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. For example, one or more nitrogen atoms of any of the heterocycles in the definition of Het1, Het2 and Het3 may be N-oxidized.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, a hydroxy substituted triazine moiety may also exist as the corresponding triazinone moiety; a hydroxy substituted pyrimidine moiety may also exist as the corresponding pyrimidinone moiety.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms in which the compounds of formula (I) can exist. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration, used herein in accordance with Chemical Abstracts nomenclature. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The compounds of formula (I) and some of the intermediates in the present invention contain one or more asymmetric carbon atoms. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms.
An interesting group of compounds are those compounds of formula (I) wherein the 6-azauracil moiety is connected to the annelated phenyl ring in the 2 or 3 position; preferably in the 2 position.
Another interesting group contains those compounds of formula (I) wherein one or more of the following restrictions apply:
p is 0, 1 or 2, preferably p is 0;
q is 0 or 1;
X1 is S, NR3 or a direct bond; more in particular a direct bond;
each R1 independently is halo, polyhaloC1-6alkyl, C1-6alkyl, C1-6alkyloxy or aryl, preferably R1 is chloro;
R2 is Het1, cyano, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15 or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxy, C1-6alkylsulfonyloxy, C1-6alkyloxycarbonyl, C3-7cycloalkyl, aryl, aryloxy, arylthio, Het1oxy and Het1thio; more in particular Het1, cyano or xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15;
each R4 independently represents C1-6alkyl, halo, polyhaloC1-6alkyl, R6 or C1-6alkyloxy;
R15 is hydrogen or C1-6alkyl, and when X2 is a direct bond, R15 may also be halo, and when X2 is C(xe2x95x90O)xe2x80x94NHxe2x80x94NH, R15 may also be phenyl;
R6 is C1-6alkylsulfonyl or aminosulfonyl;
R7 and R8 are each independently hydrogen, C1-4alkyl, Het3 or R6;
R9 and R10 are each independently hydrogen, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, Het3carbonyl, Het3 or R6;
R11 is cyano, nitro, halo, C1-4alkyloxy, formyl, NR7R8, C(xe2x95x90O)NR7R8, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, aryl, arylcarbonyl, Het3, Het4 and C(xe2x95x90O)Het3, more in particular aryl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14,
R14 is hydrogen or C1-4alkyl;
aryl is phenyl optionally substituted with one, two or three substituents each independently selected from nitro, cyano, halo, hydroxy, C1-4alkyl, C3-7cycloalkyl, C1-4alkyloxy, formyl, polyhaloC1-4alkyl, NR9R10, C(xe2x95x90O)NR9R10, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Oxe2x80x94R6, phenyl, C(xe2x95x90O)Het3 and C1-4alkyl substituted with hydroxy, C1-4alkyloxy, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 or NR9R10, more in particular phenyl optionally substituted with halo or C1-4alkyl;
Het1 is a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, in particular imidazolyl, oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 or R11; preferably Het1 is oxadiazolyl or thiazolyl each independently and optionally substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl optionally substituted with R11;
Het2 is an aromatic heterocycle; more in particular furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl;
Het3 is piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkylcarbonyl, piperidinyl and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy and phenyl;
Het4 is thienyl.
Special compounds are those compounds of formula (I) wherein p is 0, 1 or 2 and each R1 is chloro; preferably p is 0.
Particular compounds are those compounds of formula (I) wherein the 6-azauracil moiety is in the 2 position, and p is 0.
Other particular compounds are those compounds of formula (I) wherein X1 is a direct bond and R2 is cyano or a monocyclic heterocycle selected from thiazolyl and oxadiazolyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one or two substituents each independently selected from R11 and C1-4alkyl optionally substituted with R11.
Preferred compounds are those compounds of formula (I) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is (CH2)r; more preferably (CH2)2.
More preferred compounds are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is optionally substituted 2-thiazolyl or 3-oxadiazolyl, the 6-azauracil moiety is in the 2 position, and p is 0.
In order to simplify the structural representation of the compounds of formula (I), the group 
will hereinafter be represented by -AZA.
Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) wherein W1 is a suitable leaving group such as, for example, a halogen atom, with an appropriate reagent of formula (III). 
Said reaction may be performed in a reaction-inert solvent such as, for example, acetonitrile, N,N-dimethylformamide, acetic acid, tetrahydrofuran, ethanol or a mixture thereof. Alternatively, in case the reagent of formula (III) acts as a solvent, no additional reaction-inert solvent is required. The reaction is optionally carried out in the presence of a base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium bicarbonate, sodiumethanolate and the like. Convenient reaction temperatures range between xe2x88x9270xc2x0 C. and reflux temperature.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
Some of the compounds and intermediates of the present invention can be prepared according to or analogous to the procedures described in EP-A-0,170,316, EP-A-0,232,932 and PCT/EP98/04191.
For instance, compounds of formula (I) may generally be prepared by cyclizing an intermediate of formula (IV) wherein L is a suitable leaving group such as, for example, C1-6alkyloxy or halo, and E represents an appropriate electron attracting group such as, for example, an ester, an amide, a cyanide, C1-6alkylsulfonyloxy and the like groups; and eliminating the group E of the thus obtained triazinedione of formula (V). The cyclization can suitably be carried out by refluxing the intermediate (IV) in acidic medium such as acetic acid and in the presence of a base such as, for example, potassium acetate. 
Depending on its nature, E can be eliminated using various art-known elimination procedures. For example when E is an amide or a cyano moiety, it can be hydrolized to a carboxylic moiety by for instance refluxing the intermediate bearing the E group in hydrochloric acid and acetic acid. The thus obtained intermediate can then be further reacted with mercaptoacetic acid or a functional derivative thereof to obtain a compound of formula (I). Said reaction is conveniently carried out at elevated temperatures ranging up to reflux temperature. 
A suitable way to prepare intermediates of formula (IV) involves the reaction of an intermediate of formula (VI) with sodium nitrite or a functional derivative thereof in an acidic medium such as for example hydrochloric acid in acetic acid, and preferably in the same reaction mixture, further reacting the thus obtained intermediate with a reagent of formula (VII) wherein L and E are as defined above, in the presence of a base such as, for example, sodium acetate. 
An interesting subgroup within the present invention are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is an optionally substituted 2-thiazolyl moiety, said compounds being represented by formula (I-a). The optionally substituted 2-thiazolyl moiety can be incorporated in the compounds of formula (I-a) at different stages of the preparation process.
For instance, scheme 1 depicts three possible ways to prepare compounds of formula (I-a). 
A first pathway involves the reaction of the cyano moiety in an intermediate of formula (VIII) to the corresponding thioamide using H2S gas in a suitable solvent such as, for example, pyridine and in the presence of a base such as, for example, triethylamine, thus obtaining an intermediate of formula (IX-a). This thioamide can then be cyclized with an intermediate of formula (XI) wherein W is a suitable leaving group such as, for example, a halogen, e.g. bromo, in a suitable solvent such as, for example, ethanol. The amino moiety in the resulting 2-thiazolyl derivative of formula (IX-b) can then be further reacted as described hereinabove to form a 6-azauracil ring, thus obtaining a compound of formula (I-a).
A second pathway to form compounds of formula (I-a) involves first the protecting of the amino moiety in an intermediate of formula (VIII) by introducing a suitable protective group P such as, for example, an alkylcarbonyl group, using art-known protection techniques. In the example of P being a alkylcarbonyl group, the intermediates of formula (VIII) can be reacted with the corresponding anhydride of formula alkylxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C(xe2x95x90O)-alkyl in an appropriate solvent such as, for example, toluene. The thus obtained intermediate of formula (X-a) can then be further reacted according to the first pathway described hereinabove. The final step, before formation of the 6-azauracil ring can be initiated after having deprotected the amino moiety using art-known deprotection techniques. In the example of P being a alkylcarbonyl group, the intermediates of formula (X-c) may be deprotected by reacting them in a suitable solvent such as, for example, ethanol, in the presence of an acid such as, for example, hydrochloric acid.
A third pathway involves first the formation of the 6-azauracil ring as described hereinabove but starting from an intermediate of formula (VIII), and subsequently reacting the thus formed compound of formula (I) wherein xe2x80x94X1xe2x80x94R2 is cyano, said compounds being represented by formula (I-c), with H2S and further reacting the compound of formula (I) wherein xe2x80x94X1xe2x80x94R2 is a thioamide, said compounds being represented by formula (I-d), with an intermediate of formula (XI) as described in the first pathway, to finally form a compound of formula (I-a).
Another interesting subgroup within the present invention are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is an optionally substituted 1,2,4-oxadiazol-3-yl moiety, said compounds being represented by formula (I-b-1). The optionally substituted 1,2,4-oxadiazol-3-yl moiety can be incorporated at the same stages of the reaction procedure as depicted for the 2-thiazolyl derivatives in scheme 1.
For instance, analogous to one of the three pathways shown in scheme 1, compounds of formula (I-b) can be prepared by reacting an intermediate of formula (VIII) as depicted in scheme 2. 
In said scheme 2, the cyano group of an intermediate of formula (VII) is reacted with hydroxylamine or a functional derivative thereof in a suitable solvent such as, for example, methanol, and in the presence of a base such as, for example, sodium methanolate. The thus formed intermediate of formula (XIII-a) is then reacted with an intermediate of formula (XIV) wherein W is a suitable leaving group such as, for example, a halogen, e.g. chloro, in an appropriate solvent such as, for example, dichloromethane, and in the presence of a base, such as, for example, N,N-(1-methylethyl)ethaneamine. The resulting intermediate of formula (XIII-b) is then cyclized to a 3-oxadiazolyl derivative of formula (XIII-c). The amino moiety in the intermediates of formula (XIII-c) can then be transformed to the 6-azauracil ring as described above.
Still another interesting subgroup within the present invention are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is an optionally substituted 1,3,4-oxadiazol-2-yl moiety, said compounds being represented by formula (I-b-2).
For instance, compounds of formula (I-b-2) can be prepared as depicted in scheme 3. 
The nitrile moiety in an intermediate of formula (XV) is transformed into a carboxylic acid moiety using art-known techniques. For instance, the nitrile derivative may be refluxed in a mixture of sulfuric acid and acetic acid in water. The carboxylic acid of formula (XVI-a) may be reacted with a chlorinating agent such as, for example, thionyl chloride, to form an acyichioride derivative of formula (XVI-b). Subsequently, the acyl chloride may be reacted with a hydrazine derivative of formula (XVII) in a suitable solvent such as, for example, dichioromethane, and in the presence of a base such as, for example N,N-(1-methylethyl)ethaneamine. The thus formed intermediate of formula (XVI-c) may be cyclized to a 1,2,4-oxadiazol-2-yl derivative of formula (XVI-d) in the presence of phosphoryl chloride. As a final step before the formation of the 6-azauracil ring as described above, the nitro group in the intermediates of formula (XVI-e) is reduced to an amino group using art-known reduction techniques such as, for instance, reducing the nitro group with hydrogen in methanol and in the presence of a catalyst such as Raney Nickel.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation such as, for example, those mentioned in PCT/EP98/04191 and the ones exemplified in the experimental part hereinafter.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials as used in the reaction procedures mentioned hereinabove are known compounds and may be commercially available or may be prepared according to art-known procedures.
IL-5, also known as eosinophil differentiating factor (EDF) or eosinophil colony stimulating factor (Eo-CSF), is a major survival and differentiation factor for eosinophils and therefore thought to be a key player in eosinophil infiltration into tissues. There is ample evidence that eosinophil influx is an important pathogenic event in bronchial asthma and allergic diseases such as, cheilitis, irritable bowel disease, eczema, urticaria, vasculitis, vulvitis, winterfeet, atopic dermatitis, pollinosis, allergic rhinitis and allergic conjunctivitis; and other inflammatory diseases, such as eosinophilic syndrome, allergic angiitis, eosinophilic fasciutis, eosinophilic pneumonia, PIE syndrome, idiopathic eosinophilia, eosinophilic myalgia, Crohn""s disease, ulcerative colitis and the like diseases.
The present compounds also inhibit the production of other chemokines such as monocyte chemotactic protein-1 and -3 (MCP-1 and MCP-3). MCP-1 is known to attract both T-cells, in which IL-5 production mainly occurs, and monocytes, which are known to act synergetically with eosinophils (Carr et al., 1994, Immunology, 91, 3652-3656). MCP-3 also plays a primary role in allergic inflammation as it is known to mobilize and activate basophil and eosinophil leukocytes (Baggiolini et al., 1994, Immunology Today, 15(3), 127-133).
The present compounds have no or little effect on the production of other chemokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, xcex3-interferon (IFN-xcex3) and granulocyte-macrophage colony stimulating factor (GM-CSF) indicating that the present IL-5 inhibitors do not act as broad-spectrum immunosuppressives.
The selective chemokine inhibitory effect of the present compounds can be demonstrated by in vitro chemokine measurements in human blood of which the test results for IL-5 are presented in the experimental part hereinafter. In vivo observations such as the inhibition of eosinophilia in mouse ear, the inhibition of blood eosinophilia in the Ascaris mouse model; the reduction of serum IL-5 protein production and splenic IL-5 mRNA expression induced by anti-CD3 antibody in mice and the inhibition of allergen- or Sephadex-induced pulmonary influx of eosinophils in guinea-pig are indicative for the usefulness of the present compounds in the treatment of eosinophil-dependent inflammatory diseases.
The present inhibitors of IL-5 production are orally active compounds.
In view of the above pharmacological properties, the compounds of formula (I) can be used as a medicine. In particular, the present compounds can be used in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases as mentioned hereinabove, more in particular bronchial asthma, atopic dertmatitis, allergic rhinitis and allergic conjunctivitis.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from eosinophil-dependent inflammatory diseases, in particular bronchial asthma, atopic dertmatitis, allergic rhinitis and allergic conjunctivitis. Said method comprises the systemic or topical administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for treating eosinophil-dependent inflammatory diseases comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclodextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxyethyl; C1-6alkylcarbonyl, particularly acetyl; C1-6alkyloxycarbonylC1-6alkyl or carboxy-C1-6alkyloxyC1-6alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C1-6alkylcarbonyloxyC1-6alkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex2-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The M.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10.
The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the D.S. ranges from 0.125 to 3.
Due to their high degree of selectivity as IL-5 inhibitors, the compounds of formula (I) as defined above, are also useful to mark or identify receptors. To this purpose, the compounds of the present invention need to be labelled, in particular by replacing, partially or completely, one or more atoms in the molecule by their radioactive isotopes. Examples of interesting labelled compounds are those compounds having at least one halo which is a radioactive isotope of iodine, bromine or fluorine; or those compounds having at least one 11C-atom or tritium atom.
One particular group consists of those compounds of formula (I) containing a radioactive halogen atom. In principle, any compound of formula (I) containing a halogen atom is prone for radiolabelling by replacing the halogen atom by a suitable isotope. Suitable halogen radioisotopes to this purpose are radioactive iodides, e.g. 122I, 123I, 125I, 131I; radioactive bromides, e.g. 75Br, 76Br, 77Br and 82Br, and radioactive fluorides, e.g. 18F. The introduction of a radioactive halogen atom can be performed by a suitable exchange reaction or by using any one of the procedures as described hereinabove to prepare halogen derivatives of formula (I).
Another interesting form of radiolabelling is by substituting a carbon atom by a 11C-atom or the substitution of a hydrogen atom by a tritium atom.
Hence, said radiolabelled compounds of formula (I) can be used in a process of specifically marking receptor sites in biological material. Said process comprises the steps of (a) radiolabelling a compound of formula (I), (b) administering this radio-labelled compound to biological material and subsequently (c) detecting the emissions from the radiolabelled compound. The term biological material is meant to comprise every kind of material which has a biological origin. More in particular this term refers to tissue samples, plasma or body fluids but also to animals, specially warm-blooded animals, or parts of animals such as organs.
The radiolabelled compounds of formula (D) are also useful as agents for screening whether a test compound has the ability to occupy or bind to a particular receptor site. The degree to which a test compound will displace a compound of formula (I) from such a particular receptor site will show the test compound ability as either an agonist, an antagonist or a mixed agonist/antagonist of said receptor.
When used in in vivo assays, the radiolabelled compounds are administered in an appropriate composition to an animal and the location of said radiolabelled compounds is detected using imaging techniques, such as, for instance, Single Photon Emission Computerized Tomography (SPECT) or Positron Emission Tomography (PET) and the like. In this manner the distribution of the particular receptor sites throughout the body can be detected and organs containing said receptor sites can be visualized by the imaging techniques mentioned hereinabove. This process of imaging an organ by administering a radiolabelled compound of formula (I) and detecting the emissions from the radioactive compound also constitutes a part of the present invention.
In general, it is contemplated that a therapeutically effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.05 mg/kg to 10 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between two or four intakes per day.